BRPI0709082A2 - substituted indazole derivatives, their manufacture and use as pharmaceutical agents - Google Patents

Abstract

SUBSTITUTED INDAZOL DERIVATIVES, THEIR MANUFACTURE AND USE AS PHARMACEUTICAL AGENTS. The present invention relates to compounds of formula I, formula I, their pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, the preparation of the aforementioned compounds, drugs containing them and their manufacture, as well as the use of the aforementioned compounds in the control or prevention of diseases such as cancer.

Description

Patent Descriptive Report for "derivatives

indazol, their manufacture and use as pharmaceutical agents ".

The present invention relates to substituted indazole derivatives, to a process for their manufacture, to pharmaceutical compositions containing them and to their manufacture as well as to the use of these compounds as pharmaceutically active agents.

Protein kinases regulate many different signaling processes by adding phosphate groups to proteins (Hunter, T., Cell 50 (1987) 823-829); particularly serine phosphorylate proteins / threoninacinases in the alcohol portion of serine or threonine residues. The deserine / threonine kinase family includes members that control cell growth, migration, differentiation, gene expression, muscle contraction, glucose metabolism, cell protein synthesis, and cell cycle regulation.

Aurora kinases are a family of serine / threonine kinases that are believed to play a key role in protein phosphorylation events that are essential for the completion of essential mitotic events. The Aurora kinase family is made up of three key members: Au-rora A, B and C (similarly known as Aurora-2, Aurora-1 and Auro-ra-3 respectively). Aurora-1 and Aurora-2 are described in Sugen US 6,207,401 and related patents and patent applications, for example, EP 0 868 519 and EP 1 051 500.

For Aurora A there is growing evidence that it is a new proto-oncogene. The Aurora A gene is extended and transcription / protein is highly expressed in a majority of human tumor cell lines and primary colorectal tumors, mam and other tumors. Aurora A overexpression has been shown to lead to genetic instability shown amplified percentomesomes and significant increase in rat aneuploid and fibroblast transforms and mouse NIH3T3 cells in vitro. Aurora A transformed NIH3T3 cells grow as tumors in nude mice (Bischoff, JR, and Plowman, GD, Trends Cell Biol. 9 (1999) 454-459; Giet, R., and Prigent, C., J. Cell Sci. 112 (1999) 3591-3601; Nigg, EA, Nat.Rev. Mol. Cell Biol. 2 (2001) 21-32; Adams, RR, et al., Trends Cell Biol.11 (2001) 49-54). In addition, Aurora A amplification is associated with aggressive and aneuploid clinical behavior (Sen, S., et al., J. Na-tl. Cancer Inst. 94 (2002) 1320-1329) and amplification of its correlate-nausea site. with poor prognosis for node-negative breast cancer patients (Isola, JJ, et al., Am. J. Pathology 147 (1995) 905-911). For these reasons, it is proposed that Aurora A overexpression contributes to cancer paraphenotype by being involved in chromosome segregation and mitotic barrier control.

Human tumor cell lines depleted of Aurora A transcripts interrupt mitosis. Consequently, specific inhibition of Aurora kinase by selective inhibitors is recognized for uncontrolled proliferation, re-establishing mitotic barrier control and conducting tumor cell apoptosis. In a xenograft model, an Aurora inhibitor thus reduces the growth rate of tumor-inducing regression (Harrington, E.A., et al., Nat. Med. 10 (2004) 262-267).

Low molecular weight inhibitors for protein kinases are widely known in the art. For inhibition of Aurora, such inhibitors are based on, that is, quinazoline derivatives as claimed in the following patents and patent applications: WO 00/44728; WO 00/47212; WO 01/21594; WO 01/21595; WO 01/21596; WO 01/21597; WO 01/77085; WO 01/55116; WO 95/19169; WO 95/23141; WO 97/42187; WO 99/06396; pyrazole derivatives as claimed in the following patents and patent applications: WO 02/22601; WO 02/22603; WO 02/22604; WO 02/22605; WO 02/22606; WO 02/22607; WO 02/22608; WO 02/50065; WO 02/50066; WO 02/057259; WO 02/059112; WO 02/059111; WO 02/062789; WO 02/066461; WO 02/068415.

Some tricyclic heterocycles or related compounds are known as erythrocyte aggregation inhibitors of Mertens, A., and others, J. Med. Chem. 30 (1987) 1279-1287; von der Saal, W., et al., J. Med. Chem. 32 (1989) 1481-1491; US 4,666,923Α; 4,695,567Α; US4,863,945Α and US 4,954,498Α.

WO 03/035065 refers to benzimidazole derivatives as kinase inhibitors, especially as inhibitors against KDR, SYK and ITK tyrosine kinases. WO 01/02369 and WO 01/53268 refer to deindazole derivatives as kinase inhibitors, especially as inhibitors against VGEF, LCK, FAK1 TEK1 CHK-1 and CDKs1 with antiproliferative activity.

Summary of the Invention

The present invention relates to tricyclic aminopyrazole derivatives of the general formula I,

on what

R1 is alkyl;

R2 and R3 are alkyl;

one of R4 and R5 is a) -X-heteroaryl, wherein heteroaryl is optionally substituted one to three times by alkyl, C (O) alkyl, alkoxy, fluorinated alkyl, fluorinated alkoxy, cyano, nitro, amino, alkylamino dialkylamino or halogen;

b) -Y-phenyl,

wherein phenyl is optionally substituted one to three times by alkyl, C (O) alkyl, carboxy, NHC (O) alkyl, alkoxy, fluorinated alkyl, fluorinated alkoxy, cyano, hydroxy, nitro, amino alkylamino, dialkylamino, C (O) alkyl- NH-, alkyl-S (O) 2 NH-, halogen, 2,4-dioxa-pentan-1,5-diyl or 2,5-dioxahexan-1,6 diyl;

or wherein phenyl is substituted once by phenyl; or

c) -Z-cycloalkyl;

25 and the other of R4 and R5 is hydrogen;

X is a single bond, -CH = CH- or -C ^C-;

Y is a single bond, -CH = CH- or -CsC-, and all pharmaceutically acceptable salts thereof.

The compounds according to this invention show activity as Aurora family kinase inhibitors, especially as Aurora A kinase inhibitors, and may therefore be useful for the treatment of diseases mediated by said kinase. Inhibition of Aurora A leads to cell cycle disruption in the G2 phase of the cell cycle and exerts an antiproliferative effect on tumor cell lines. This indicates that Auro-ra A inhibitors may be useful in the treatment of, e.g., hyperproliferative diseases such as cancer, and in particular colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma cancers. , neuro-blastoma, cervical, kidney or kidney, eukemias or lymphomas. Treatment of acute myelogenous leukemia (AML, acute lymphocytic leukemia (ALL) and gastrointestinal tumoral tumor (GIST) is included.

The objects of the present invention are the compounds of formula

I and their tautomers, pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, their use as Aurora kinase inhibitors, the preparation of the aforementioned compounds, medicaments containing them and their manufacture, and the use of the above compounds in treating, controlling or preventing disease, especially disease and disorders as mentioned above, such as tumors or cancer (e.g., colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovaries, melanomas, neuroblastomas, cervicals, kidney kidneys, leukemias or lymphomas) or in the manufacture of corresponding medicines.

Detailed Description of the Invention

The term "alkyl" as used herein means a saturated straight or branched chain hydrocarbon having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, n-pentyl, n-hexyl.

The term "alkoxy" as used herein means an alkyl-O- group, where alkyl is defined as above.

The term "alkylamino" when used herein means an alkyl-NH- group wherein alkyl is defined as above.

The term "dialkylamino" as used herein means an (alkyl) 2 N- group, wherein alkyl is defined as above.

The term "halogen" as used herein means fluorine, chlorine or bromine, preferably fluorine or chlorine.

The term "fluorinated alkyl" as used herein means an alkyl group as defined above which is substituted one or more times, preferably one to six and more preferably one to three times, by fluorine. Examples are difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, and the like, preferably trifluoromethyl.

The term "fluorinated alkoxy" as used herein means an alkoxy group as defined above, which is substituted one or more times, preferably one to six and more preferably one to three times, with fluorine.

Examples are difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, similar perfluorooxy, preferably trifluoromethoxy.

The term "cycloalkyl" as used herein means a saturated monocyclic hydrocarbon ring having from 3 to 7, preferably 3 to 6, ring atoms. Examples of such saturated carbocyclic groups are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloeptyl, preferably cyclopentyl or cyclohexyl.

The term "heteroaryl" means a mono- or bicyclic aromatic ring of 5 to 10, preferably 5 to 6 ring atoms, containing up to 3, preferably 1 or 2 heteroatoms independently selected from Ν, O or S and remaining ring atoms that are carbon atoms. Examples of such heteroaryl groups include pyrrolyl, imidazolyl, pi-razolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl, benzothiophenyl, isoquinolyl, quinazolinyl, quinoxalini-1a and the like, preferably pyrazolyl, triazolyl, tetrazolyl, thienyl, pyridylor pyrimidyl.

If the phenyl group of -Y-phenyl in the definition of R4 and R5 is substituted, such phenyl group is preferably substituted once or twice.

If the phenyl group of -Y-phenyl in the definition of R4 and R5 is substituted by 2,4-dioxa-pentan-1,5-diyl or 2,5-dioxahexan-1,6-diyl, it is substituted. preferably once by 2,4-dioxa-pentan-1,5-diyl or 2,5-dioxa-hexan-1,6-diyl and forms together with 2,4-dioxa-pentan-1,5-diyl. diyl or the substituted 2,5-dioxahexan-1,6-diyl, a benzo [1,3] dioxolyl or a 2,3-dihydro-benzo [1,4] dioxinyl moiety.

When used herein, for mass spectrometry (MS), the term "ESI +" refers to the positive electrospray ionization mode, the term "ESI-" refers to the negative electrospray ionization mode, the term "API +" refers to positive at-atmospheric pressure ionization mode and the term "API-" refers to negative atmospheric pressure ionization mode.

When used herein, with respect to nu-clear magnetic resonance (NMR), the term "DMSO" refers to deuterated dimethyl sulfoxide.

When used herein, the term "therapeutically effective amount" of a compound means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong survival of the subject being treated. Determination of a therapeutically effective amount is within the skill of the art.

The therapeutically effective amount or dosage of a compound according to this invention may vary within broad limits, and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case, including the specific compound (s) to be administered, the routine of administration, the condition to be treated as well as the patient to be treated. In general, in case of oral or parenteral administration to adult humans weighing approximately 70 kg a daily dosage of from about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage may be administered as a single dose or in divided doses, or for parenteral administration may be given as continuous infusion.

When used herein, a "pharmaceutically acceptable carrier" or a "pharmaceutically acceptable adjuvant" is intended to include any and all material compatible with pharmaceutical administration including solvents, dispersion media, coatings, antifungal antibacterial agents, absorption and isotonic retarding agents; and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with the active compound, their use in the compositions of the invention is considered. Additional active compounds may likewise be incorporated into the compositions.

The compounds of formula I may exist in different tautomeric forms and in varying mixtures thereof. All tautomeric forms of the compounds of formula I and mixtures thereof are an object of the invention. For example, the imidazole portion of the Ipode tricyclic ring system exists in two tautomeric forms, as shown here below:

<formula> formula see original document page 8 </formula>

formula I.

One embodiment of the invention is compounds according to formula I, wherein

one of R4 and R5 is a) -X-heteroaryl, wherein heteroaryl is optionally substituted one to three times, preferably once or twice, by alkyl-1a or alkoxy; b) -Y-phenyl,

wherein phenyl is optionally substituted one to three times, preferably once or twice, by alkyl, C (O) alkyl, alkoxy, fluorinated alkyl, nitro, dialkylamino, halogen or 2,4-dioxapentanyl. 1,5-diyl, or wherein phenyl is substituted once by phenyl; or

c) -Z-cycloalkyl;

and the other of R4 and R5 is hydrogen;

X is a simple bond;

Y is a single bond, -CH = CH- or -C ^C-; and

Z is -CH = CH-.

Another embodiment of the invention is the compounds according to formula I, wherein

one of R4 and R5 is -X-heteroaryl, wherein heteroaryl is optionally substituted one to three times by alkyl or alkoxy, and the other of R4 and R5 is hydrogen;

Another embodiment of the invention is the compounds according to formula I, wherein

one of R4 and R5 is -X-heteroaryl, wherein heteroaryl is optionally substituted one to three times by alkyl or alkoxy, and the other of R4 and R5 is hydrogen; and

X is a simple bond.

Such compounds, for example, may be selected from the group consisting of:

5-Ethyl-7,7-dimethyl-2- [5- (1H - [1,2,4] triazol-3-yl) -1H-indazol-3-yl] -5,7-dihydro-3H -imidazo [4,5 -] indol-6-one;

5-Ethyl-7,7-dimethyl-2- [6- (1H - [1,2,4] triazol-3-yl) -1H-indazol-3-yl] -5,7-dihydro-3H -imidazo [4,5 -] indol-6-one;

5-Ethyl-7,7-dimethyl-2- [5- (1H-tetrazol-5-yl) -1H-indazol-3-yl] -5,7-dihydro-3H-imidazo [4,5-flindol-2-one] 6-one;

5-Ethyl-7,7-dimethyl-2- (6-thiophen-3-yl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one one;

5-Ethyl-7,7-dimethyl-2- [6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-yl] -5,7-dihydro-3W-imidazo [ 4,5 -] indol-6-one;

5-Ethyl-7,7-dimethyl-2- (6-pyridin-3-yl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f / indol-6 -one;

5-Ethyl-2- [6- (6-methoxy-pyridin-3-yl) -1H-indazol-3-yl] -7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5 indol-6-one;

5-Ethyl-7,7-dimethyl-2- (6-pyridin-4-yl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f-indol-6 -one;

5-Ethyl-77-dimethyl-2- (6-thiophen-2-yl-1H-indazol-3-yl) -57-dihydro-3H-imidazo [4,5-flindol-6-one;

5-Ethyl-2- [5- (6-methoxy-pyridin-3-yl) -1H-indazol-3-yl] -7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5 indol-6-one; compound with acetic acid;

5-Ethyl-77-dimethyl-2- (5-thiophen-3-yl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5- [jindol-6-one; compound with acetic acid;

5-Ethyl-7,7-dimethyl-2- [5- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-yl] -5,7-dihydro-3H-imidazo [ 4,5-flindol-6-one; compound with acetic acid;

5-Ethyl-7,7-dimethyl-2- (5-pyriclin-3-yl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-flindol-6-one ;

5-Ethyl-7,7-dimethyl-2- (6-pyrimidin-5-yl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-flindol-6-one ;

5-Ethyl-7,7-dimethyl-2- (6-pyridin-2-yl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f-indol-6 -one;

5-Ethyl-7,7-dimethyl-2- (5-pyrimidin-5-yl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f-indol-6 -one;

5-Ethyl-77-dimethyl-2- (5-pyridin-2-yl-1H-indazol-3-yl) -57-dihydro-3H-imidazo [4,5-] indol-6-one; and

5-Ethyl-7,7-dimethyl-2- [6- (1H-pyrazol-4-yl) -1H-indazol-3-yl] -5,7-dihydro-3H-imidazo [4,5- flindol-6-one.

Another embodiment of the invention is the compounds according to formula I, wherein

one of R4 and R5 is -Y-phenyl,

wherein phenyl is optionally substituted one to three times by alkyl, C (O) alkyl, alkoxy, fluorinated alkyl, nitro, dialkylamino, halogen or 2,4-dioxa-pentan-1,5-diyl ; or wherein phenyl is substituted once by phenyl;

and the other of R4 and R5 is hydrogen.

Another embodiment of the invention is the compounds according to formula I, wherein

one of R4 and R5 is -Y-phenyl,

wherein phenyl is optionally substituted one to three times by C (O) - alkyl, carboxy, alkoxy, nitro, dialkylamino or halogen; or wherein phenyl is substituted once by phenyl, and the other of R4 and R5 is hydrogen; and

Y is a simple bond.

Such compounds, for example, may be selected from the group consisting of:

2- [6- (4-Dimethylamino-phenyl) -1H-indazol-3-yl] -5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-] indol-2-one 6-one;

2- [6- (4-Acetyl-phenyl) -1H-indazol-3-yl] -5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5 - /] indole -6-one;

4- [3- (5-Ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo [4,5- / lindol-2-yl) -1 N -indazolic acid 6-yl] benzoic acid;

2- (6-Benzo [1,3] dioxol-5-yl-1H-indazol-3-yl) -5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5 flindol-6-one;

2- [6- (3-Dimethylamino-phenyl) -1H-indazol-3-yl] -5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-] indol-2-one 6-one;

5-Ethyl-7,7-dimethyl-2- [6- (3-nitro-phenyl) -1H-indazol-3-yl] -5,7-dihydro-3H-imidazo [4,5- /] indol-2-one 6-one;

2- [5- (4-Dimethylamino-phenyl) -1H-indazol-3-yl] -5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-flindol-6-one one;

2- [5- (3-Dimethylamino-phenyl) -1H-indazol-3-yl] -5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-] indole -6-one;

2- (5-Benzo [1,3] dioxol-5-yl-1H-indazol-3-yl) -5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5 indol-6-one; compound with acetic acid;

5-Ethyl-7,7-dimethyl-2- (6-phenyl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-] indol-6-one; and

2- [6- (3,5-Dimethoxy-phenyl) -1H-indazol-3-yl] -5-ethyl-7J-dimethyl-5'-dihydro-3H-imidazo [4,5- [] indol-6- one.

Another embodiment of the invention is the compounds according to formula I, wherein

one of R4 and R5 is -Y-phenyl,

wherein phenyl is optionally substituted one to three times by alkoxy, fluorinated alkyl, nitro or halogen; or wherein phenyl is substituted once for phenyl, and the other of R4 and R5 is hydrogen; and Y is -CH = CH-.

Such compounds, for example, may be selected from the group consisting of:

5-Ethyl-7,7-dimethyl-2- [6 - ((E) -styryl) -1H-indazol-3-yl] -5,7-dihydro-3 / - / - imidazo [4,5- flindol-6-one;

5-Ethyl-2- {6 - [(E) -2- (4-fluoro-phenyl) -vinyl] -1H-indazol-3-yl} -7,7-dimethyl-5,7-dihydro-3H- imidazo [4,5 -] indol-6-one;

2- [6 - ((E) -2-Biphenyl-4-yl-vinyl) -1H-indazol-3-yl] -5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo [ 4,5 -] indol-6-one;

5-Ethyl-2- {6 - [(E) -2- (4-methoxy-phenyl) -vinyl] -1H-indazol-3-yl} -7,7-dimethyl-5,7-dihydro-3H -imidazo [4,5-flindol-6-one;

5-Ethyl-7,7-dimethyl-2- {6 - [(E) -2- (4-trifluoromethyl-phenyl) -vinyl] -1H-indazol-3-yl} -5,7-dihydro-3H- imidazo [4,5 -] indol-6-one;

2- {6 - [(E) -2- (4-Chloro-phenyl) -vinyl] -1H-indazol-3-yl} -5-ethyl-7,7-dimethyl-5,7-dihydro-3H- imidazo [4,5 -] indol-6-one;

5-Ethyl-2- {6 - [(E) -2- (3-fluoro-phenyl) -vinyl] -1H-indazol-3-yl} -7,7-dimethyl-5,7-dihydro-3 / imidazo [4,5- indol-6-one; and

5-Ethyl-7,7-dimethyl-2- {6 - [(E) -2- (3-nitro-phenyl) -vinyl] -1H-indazol-3-yl} -5,7-dihydro-3H -imidazo [4,5 -] indol-6-one; compound with acetic acid.

Another embodiment of the invention is compounds according to formula I, wherein one of R 4 and R 5 is -Y-phenyl, wherein phenyl is optionally substituted one to three times by alkyl, C (O) -alkyl, alkoxy, fluorinated alkyl, nitro, dialkylamino, halogen or 2,4-dioxa-pentan-1,5-diyl; or wherein phenyl is substituted once by phenyl;

and the other of R4 and R5 is hydrogen; and Y is -C = C-.

Such a compound is for example: 5-Ethyl-77-dimethyl-2- (6-phenylethynyl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5- [] indol-6-one one.

Another embodiment of the invention are the compounds according to

of formula I, wherein one of R4 and R5 is -Z-cycloalkyl, and the other of R4 and R5 is hydrogen.

Such a compound is for example: 2- [6 - ((E) -2-Cyclohexyl-vinyl) -1H-indazol-3-yl] -5-ethyl-7,7-dimethyl-5,7-dihydro-3H -imidazo [4,5 -] indol-6-one.

Another embodiment of the invention are compounds according to formula I, wherein

R4 is a) -X-heteroaryl, wherein heteroaryl is optionally substituted one to three times by alkyl or alkoxy;

b) -Y-phenyl, wherein phenyl is optionally substituted one to three times by alkyl, C (O) alkyl, alkoxy, fluorinated alkyl, nitro, dialkylamino, halogen or 2,4-dioxa-pentan-1 , 5-diyl; or wherein phenyl is substituted once for phenyl; or

c) -Z-cycloalkyl;

R5 is hydrogen;

X is a simple bond;

Y is a single bond, -CH = CH- or -C ^C-; and

Z is -CH = CH-.

Another embodiment of the invention is the compounds according to formula I, wherein

R4 is -X-heteroaryl, wherein heteroaryl is optionally substituted one to three times by alkyl or alkoxy;

R5 is hydrogen; and

X is a simple bond.

Another embodiment of the invention is the compounds according to formula I, wherein

R 4 is -Y-phenyl, wherein phenyl is optionally substituted three times by alkyl, C (O) alkyl, alkoxy, fluorinated alkyl, nitro, dialkylamino, halogen or 2,4-dioxa-pentan-1. , 5-diyl; or wherein phenyl is substituted once by phenyl;

R5 is hydrogen; and

Y is a single bond, -CH = CH- or -C = C-.

Another embodiment of the invention is the compounds according to formula I, wherein

R4 is -Z-cycloalkyl;

R5 is hydrogen; and

Z is -CH = CH-.

Another embodiment of the invention is the compounds according to formula I, wherein

R5 is a) -X-heteroaryl, wherein heteroaryl is optionally substituted one to three times by alkyl or alkoxy;

b) -Y-phenyl, wherein phenyl is optionally substituted one to three times by alkyl, C (O) alkyl, alkoxy, fluorinated alkyl, nitro, dialkylamino, halogen or 2,4-dioxa-pentan-1 , 5-diyl; or wherein phenyl is substituted once for phenyl; or

c) -Z-cycloalkyl;

R4 is hydrogen;

X is a simple bond;

Y is a single bond, -CH = CH- or -C ^C-; and

Z is -CH = CH-.

Another embodiment of the invention is the compounds according to formula I, wherein

R5 is -X-heteroaryl, wherein heteroaryl is optionally substituted one to three times by alkyl or alkoxy R4 is hydrogen; and

X is a simple bond.

Another embodiment of the invention is the compounds according to formula I, wherein

R5 is -Y-phenyl, where phenyl is optionally substituted a

three times per alkyl, C (O) alkyl, alkoxy, fluorinated alkyl, nitro, dialkylamino, halogen or 2,4-dioxa-pentan-1,5-diyl; or wherein phenyl is substituted once by phenyl;

R4 is hydrogen; and

Y is a single bond, -CH = CH- or -CsC-.

Another embodiment of the invention is the compounds according to formula I, wherein R 5 is -Z-cycloalkyl;

R4 is hydrogen; and

Z is -CH = CH-.

Another embodiment of the invention is a process for preparing the compounds of formula I by reacting a compound of formula V.

<formula> formula see original document page 15 </formula>

formula V,

wherein R1, R2 and R3 are as given above for formula I, one of Fg4 and Fg5 represents a functional group selected from bromine, iodine, boronic acids or boronic acid esters and the other of Fg4 and Fg5 is hydrogen, with a compound of formula V 1a or V 1b, R 4 -G or R 5 -G 5 Formula V 1a formula V 1b, wherein R 4 and R 5 have the meaning given above for formula I and G represents a functional group selected from the group consisting of: hydrogen, bromine, iodine, boronic acids and boronic acid esters, provided that if G is bromine or iodine, Fg4 or Fg5 is boronic acid or a boronic acid ester, and if G is hydrogen, boronic acid or boronic acid ester, Fg4 or Fg5 whether bromine or iodine,

to produce the compounds of formula I

<formula> formula see original document page 16 </formula>

formula I,

wherein R1, R2, R3, R4 and R5 have the above meaning for formula I,

b) isolating the compounds of formula I; and

c) if desired, converting the compounds of formula I into their pharmaceutically acceptable salts.

The compounds of formula I, or a pharmaceutically acceptable salt thereof, which are objects of the present invention may be prepared by any process known to be applicable to the preparation of chemically related compounds. Such processes, when used to prepare a compound of formula I, or a pharmaceutically acceptable salt thereof, are illustrated by the following representative schemes 1 to 7 and examples wherein, unless otherwise stated, R 1, R 2, R 3 R 4 and R 5 have the foregoing given meaning for formula I. Required departmental materials are either commercially available or they may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying examples and literature cited below with respect to Schemes 1 through 7. Alternatively, necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary experience of an organic chemist.

A routine for the preparation of compounds of formula I starts from the diamines of formula II.

<formula> formula see original document page 17 </formula> formula Il

In formula II, R 11 R 2 and R 3 have the meaning as given above for formula I.

The synthesis of diamines of formula II or precursors thereof are described in Mertens, A., et al., J. Med. Chem. 30 (1987) 1279-1287; vonder Saal, W., et al., J. Med. Chem. 32 (1989) 1481-1491; US 4,666,923A, US 4,695,567A, US 4,863,945A, US 4,985,448A and DE 34 10 168. For example, the diamines of formula II can be synthesized as shown in Scheme 1a:

<formula> formula see original document page 17 </formula>

Scheme 1a

In Scheme 1a, R1, R2 and R3 have the meaning as set forth above for formula I, unless R1 is not hydrogen, and L represents an leaving group such as iodine, bromine, chlorine, triflate, similar.

In an alternative procedure, diamines of formula II may be obtained by an alkylation of diamines of formula III as shown in scheme 1b. Diamines of formula III may be synthesized according to scheme 1 omitting step 5.

<formula> formula see original document page 18 </formula>

Scheme 1b

In Scheme 1b, R11 R2 and R3 have the meaning as determined by

above for formula I, unless R1 is not hydrogen, and L represents a leaving group such as iodine, bromine, chlorine, triflate, and the like. The alkylation reaction is typically performed in the presence of a base such as sodium hydride, potassium hydride, and the like, especially sodium hydride, in inert solvents such as dimethylformamide (DMF), N-methylpyrrolidinone ( NMP), tetrahydrofuran, and the like.

Diamines of formula II are subsequently employed in the formation of the imidazole ring system of formula I. Different synthetic reaction series for this cyclization are described in the literature (e.g., see Mertens, A., et al., J). Med. Chem 30 (1987) 1279-1287 and US 4,695,567A).

For example, as shown in Scheme 2, diamines of formula IIa may be reacted with carboxylic acids (indazole compounds of formula IV, where A is hydroxy), chloride acids (indazole compounds of formula IV, where A is chlorine) , aldehydes (indazole compounds of formula IV, where A is hydrogen), methyl carboxylates (indazole compounds of

formula IV, wherein A is methoxy) or activated esters (indazold compounds of formula IV, wherein A is for example hydroxybenzotriazole). For detailed procedures see, Mertens, A., et al., J. Med. Chem. 30 (1987) 1279-1287 and US 4,695,567A.

<formula> formula see original document page 18 </formula>

In Scheme 2, R 1, R 2 and R 3 are as defined above for formula I and A is hydroxy, chloro, hydrogen, methoxy or for example hydroxybenzotriazole. One of the substituents Fg4 and Fg5 is a functional group suitable for conversion to R4 and R5 and the other of Fg4 and Fg5 is hydrogen. If Fg4 or Fg5 is a functional group suitable for conversion to R4 or R5, such a functional group is selected from the group consisting of: carboxy, cyano, bromine, iodine, triflate, -ZnCl1 boronic acids, boronic acid esters ( for example, boronic acid pinacolesters) and trialkylstannanes (e.g. Me3Sn, Bu3Sn). Preferably, such a functional group is selected from the group consisting of: carboxy, cyano, bromine, iodine, boronic acids and boronic acid esters (e.g. boronic acid pinacolesters). Examples for conversion to R4 and R5 (which have the meaning as defined above for formula I) are described in Schemes 5-7.

Indazoles of formula IV are commercially available or they may be prepared by different synthetic routines according to the nature of "A". If "A" is hydroxy, the corresponding 3-indazolecarboxylic acids are named IVa and may be manufactured for example as shown in the following scheme 3.

<formula> formula see original document page 19 </formula>

Scheme 3

In scheme 3, Fg4 and Fg5 have the meaning as given above for scheme II. As described in Snyder1 H.R., et al., J. Am.Chem. Sound. 74 (1952) 2009-2012, 3-indazolecarboxylic acids of formula IIIa may be prepared from basic ring opening isatins, followed by amino group diazotization, reduction to hydrazine and condemnation to yield the desired indazole.

The necessary isatins are commercially available or can be obtained by standard organic chemistry procedures, for example by reaction of the corresponding aniline with oxalyl chloride. The reaction begins with N-acylation, followed by intramolecular acylation which may be catalyzed by Lewis acids. (e.g., Piggott, MJ and Wege, D., Australian Journal of Chemistry 53 (2000) 749-754; March, J., Advanced Organic Chemistry 4th ed., John Wiley & Sons, New York (1992) 539-542). Most often, the corresponding aniline is reacted with chloral hydrate (2,2,2-trichlor-1,1-ethanediol) and hydroxylamine (hydrochloride) (by hydroxyiminoacetamides) in a cyclization reaction to the desired isatines (eg Sheibley , FE, and McNuIti, JS, J. Org. Chem. 21 (1956) 171-173; Lisowski, V., et al., J. Org. Chem. 65 (2000) 4193-4194).

If "A" is hydrogen, the corresponding 1H-indazol-3-carbaldehydes are named IVb and may be manufactured for example as shown in Scheme 4 below.

<formula> formula see original document page 20 </formula>

Scheme 4

In scheme 4, Fg4 and Fg5 have the meaning as given above in scheme 4 for scheme II. The compounds of formula IVb may be synthesized from indoles suitably substituted by NaNO2 / HCl treatment as described for example in Sall, D.J., et al., J. Med. Chem. 40 (1997) 2843-2857.

Compounds of formula I wherein R 4 or R 5 have the meaning as defined above may be prepared for example by a palladium catalyzed coupling reaction as shown in scheme 5 between a compound of formula V wherein R 1, R 2 and R 3 have the meaning as defined above and Fg4 and Fg5 represent a suitable functional group for coupling reactions such as bromine, iodine, triflate, -ZnCl, boronic acids, boronic acid pinacoesters and trialkylstannanes (e.g. Me3Sn, Bu3Sn) and a compound of formula V1a or V1b: R4-G or R5-G

formula Vla formula Vlb

wherein R4 and R5 have the meaning as defined above and G represents a functional group suitable for coupling reactions, and compatible with Fg1 as described above. G is selected from the group consisting of: hydrogen, bromine, iodine, triflate, -ZnCl, boronic acids, boronic acid esters (eg boronic acid pinacolesters) and trialkylestans (e.g. Me3Sn, Bu3Sn). Preferably G is selected from the group consisting of: hydrogen, bromine, iodine, boronic acids and boronic acid esters.

<formula> formula see original document page 21 </formula>

Scheme 5

This reaction can be, for example, but not limited to, a palladium catalyzed cross coupling reaction (G is boronic acid, boronic acid pinacolester, etc. and Fg is bromine or iodine or Fg is boronic acid, boronic acid pinacolester, etc. and G is bromine or iodine (see, for example, Miyaura, N., et al., Chem. Rev. 95 (1995) 2457; Miyaura, N., et al., Synth. Commun., 11 (1981) 513), a reaction. type Negishi (G is ZnCI, etc.) and Fg is bromine or iodine or Fg is ZnCI, etc. and G is bromine or iodine; see for example, Negishi, E., et al., J. Org. Chem. 42 (1977) 1821) or a Stille type reaction (G is trialkylstannane, for example Me3Sn, Bu3Sn and Fg is triflate, bromine or iodine or Fg is trialkylstanane, for example Me3Sn, Bu3Sn and G is triflate, bromine or iodine; for example Stille, JK, Angew. Chem. 1986,98,504).

Intermediates of formulas V, wherein Fg is a boronic acid, a boronic acid pinacolesters or trialkyl stannane etc., can be obtained for example from the corresponding halides (Fg is bromine or iodine) by standard procedures of organic chemistry. For example, compounds of formula V wherein Fg is a boronic acid pinacolester may be prepared from the bromide by a palladium catalyzed coupling (e.g., PdCl2 (dppf) -CH2Cl2) complex with pinacolbo-rano or bis (pinacolato). ) diboro. For example, compounds of formula V, wherein Fg is trialkylstannane, may be prepared from the bromide by a palladium catalyzed coupling (e.g., Pd-CI2 (MeCN) 2 complex) with hexahyldyldine tin alkyldine.

The palladium catalyzed coupling reaction may be of the same form, for example, but not limited to, of the Sonogashira type (Fg is for example Br, I or OTf, G is hydrogen and R4 or R5 is an optionally substituted phenylethynyl group or an optionally substituted heteroaryethylinyl group). See, for example, Sonogashira, K., et al., Tetrahedron Lett. 16 (1975) 4467-4470; Sonogashira, K., J. Organomet. Chem. 653 (2002) 46-49).

The palladium catalyzed coupling reaction can be of the same form as, but not limited to, the Heck type (Fg is for example, Br, I or OTf, G is hydrogen and R4 or R5 is an optionally substituted styryl group or a optionally substituted heteroarylethenyl group (see, for example, Heck, RF, et al., J. Org. Chem. 37 (1972) 2320).

Compounds of formula I, wherein R4 or R5 is a triazole are non-mid-1a and may be prepared for example from the corresponding carboxylic acids (compounds of formula V, wherein Fg4 or Fg5 is CO-OH, which are named Va) as shown in the following scheme 6 (see for example, Ankersen, M., et al., Bioorg. Med. Chem. Lett. 7 (1997) 1293-1298 or Lin, Y., et al., J. Org. Chem. 44 (1979) 4160-4164):

<formula> formula see original document page 22 </formula> Scheme 6

The carboxylic acids are converted to the amides which are reacted with α-β-dimethylformamide dimethyl acetal. Acylamidines obtained are cyclized by heating with hydrazine in glacial acetic acid to yield the desired 1,2,4-triazoles.

Compounds of formula I1 wherein R4 or R5 is a tetrazole, are Ib-labeled and may be prepared for example from the corresponding nitriles (compounds of Formula V, wherein Fg4 or Fg5 is CN, which are Vb-nominated), as shown in the following scheme 7 (see, for example, EP0512675A1 or Ankersen, M., et al., Bioorg. Med. Chem. Lett. 7 (1997) 1293-1298):

<formula> formula see original document page 23 </formula> Scheme 7

Co-loading of nitriles with trimethyl tin azide leads to the formation of the tetrazole ring system.

Certain substituents on the R4 or R5 groups may not be inert to the conditions of the synthesis sequences described above and may require protection by standard protecting groups known in the art. For example, an amino or hydroxyl group may be protected as a deacetyl or tert-butyloxycarbonyl (BOC) derivative. Alternatively, some substituents may be derived from others at the end of the reaction sequence. For example, a compound of formula I may be synthesized to support a nitro, a cyano, an ethoxycarbonyl, an ether, a sulfonic acid substituent in the R4 or R5 group, the substituents of which are finally converted to an a) amino group (e.g. by reduction of a nitro group, reduction of a groupocyan or cleavage of a suitable amino protecting group (for example, removal of a BOC group with trifluoroacetic acid (TFA))), b) alkylamino group (for example, by reductive amination of an amino group), c) dialkylamino group (e.g. by alkylation of an amino group, reduction of an appropriate acylamino group with lithium aluminum hydride or Eschweiler-Clarke reaction with an appropriate amino or alkylamino group), d) acylamino group (e.g. by amide formation of an amino group, for example with appropriate acyl halides or with appropriate carboxylic acids after their activation with 1,1'-carbonyldiimidazole (CDI), 1-hydrochloride. et yl-3- [3-dimethylaminopropyl] carbodiimide (EDC), etc.), e) alkylsulfonylamino group (for example by reaction of an amino group with sulfonyl chloride), f) arylsulfonylamino group substituent ( for example by reacting an amino group with sulfonyl chloride), g) hydroxyl group - (for example by cleavage of a suitable hydroxy protecting group (eg hydrogenolytic removal of a benzyl ether or oxidative cleavage of a p-methoxy benzyl ether) or fluoride-assisted cleavage of the silyl-protecting group), h) ether group - (for example, by synthesis of Williamson ether from a hydroxyl group), i) carboxamide group (for example, by formation of a carboxylic acid group with appropriate amines after activation of the carboxylic acid group with CDI, EDC, etc. or conversion to an acyl chloride), or j) sulfonamide group by standard procedures.

Medicaments containing a compound of the present invention or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are an object of the present invention, as is a process for their manufacture, comprising bringing one or more compounds of the present invention and / or pharmaceutically acceptable salts and, if desired. , one or more other therapeutically valuable substances in a galenic administration form together with one or more therapeutically inert carriers.

According to the invention, the compounds of the present invention as well as pharmaceutically acceptable salts thereof are useful in controlling or preventing disease. Based on their inhibition of Aurora tyrosine kinases and / or their antiproliferative activity, said compounds are useful for treating diseases such as cancer in humans or animals and for producing corresponding drugs. Dosage depends on various factors such as mode of administration, species, age and / or individual health status.

One embodiment of the invention is a pharmaceutical composition containing one or more compounds according to formula I, together with pharmaceutically acceptable excipients.

Another embodiment of the invention is a pharmaceutical composition which contains one or more compounds of formula I as active ingredients together with pharmaceutically acceptable adjuvants for the treatment of diseases mediated by improper activation of the Aurora family tyrosine kinases.

Another embodiment of the invention is a pharmaceutical composition containing one or more compounds according to formula I as active ingredients together with pharmaceutically acceptable adjuvants for inhibiting tumor growth.

Another embodiment of the invention is a pharmaceutical composition containing one or more compounds of formula I as active ingredients together with pharmaceutically acceptable adjuvants for the treatment of colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma , cervical, kidney or kidney, eukemias or lymphomas.

Another embodiment of the invention is a pharmaceutical composition which contains one or more compounds of formula I as active ingredients together with pharmaceutically acceptable adjuvants for the treatment of acute myelogenous (AML), acute lymphocytic leukemia (ALL) and gastrointestinal tumorestromal (GIST).

Another embodiment of the invention is the use of one or more compounds of formula I for the manufacture of medicaments for the treatment of diseases mediated by improper activation of tyrosine kinases of the Aurora family.

Another embodiment of the invention is the use of a compound of formula I for the manufacture of corresponding medicaments for inhibiting tumor growth.

Another embodiment of the invention is the use of a compound of formula I for the manufacture of corresponding medicaments for the treatment of colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma cancer. , neuroblastoma, cervical, kidney or kidney, eukemias or lymphomas.

Another embodiment of the invention is the use of a compound of formula I for the manufacture of medicaments for the treatment of acute myelogenous leukemia (AML) and gastrointestinal stromal tumor (GIST).

Another embodiment of the invention is the use of the compounds of formula Ia as inhibitors of Aurora tyrosine kinase.

Another embodiment of the invention is the use of the compounds of formula I as antiproliferating agents.

Another embodiment of the invention is the use of one or more compounds of formula I for the treatment of cancer.

The compounds according to the present invention may exist in the form of pharmaceutically acceptable salts thereof. The term "pharmaceutically acceptable salt" refers to conventional acid addition salts which maintain the biological effectiveness and properties of the compounds of formula I and are formed of suitable non-toxic organic or inorganic acids. Sample acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as such as p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, ethanesulfonic acid and the like. Chemical modification of a pharmaceutical compound (i.e. a drug) into a salt is a technique well known to pharmaceutical chemists for improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, for example, Stahl, P. H., and Wermut, G., (editors), Handbook of Pharmaceuticalsalts, Verlag Helvetica Chimica Acta (VHCA), Zürich, (2002), or Bastin, R.J., and others, Organic Proc. Res. Dev. 4 (2000) 427-435.

The compounds of formula I may contain one or more chiral centers and may then be present in an optically active or a racemic form. Racemates may be separated according to methods known in the enantiomers. For example, diastereomeric salts which may be separated by crystallization are formed from racemic mixtures by reaction with an optically active acid such as, for example, D- or L-camphorsulfonic acid. Alternatively, the separation of the enantiomers may be obtained in the same manner using chromatography on chiral HPLC (HPLC: High Performance Liquid Chromatography) phases which are commercially available.

Pharmacological activity

The compounds of formula I and their pharmaceutically acceptable salts have valuable pharmacological properties. These compounds have been found to show activity as inhibitors of the Au-rora kinase family and likewise show antiproliferative activity. Accordingly, the compounds of the present invention are useful in the therapy and / or prevention of diseases with known overexpression of the Aurora family kinases, preferably Aurora A, especially in the therapy and / or prevention of diseases mentioned above. The activity of compounds present as inhibitors of the Aurora kinase family is demonstrated by the following biologic assay:

ICnS Determination for Aurora A Assay Principle Inhibitors

Aurora A is a serine threonine kinase involved in spindle assembly and chromosome segregation.

The assay is typically an ELISA type assay where substrate (GST-Histone H3) is coupled to the assay plate and is phosphorylated by kinase. Phosphorylation is detected by a mouse antiphosphopeptide mAb and an HRP-labeled anti-mouse pAb. The assay is validated for IC5O-

Kinase activities were measured by Enzyme-Linked Immunosorbent Assay (ELISA): Maxisorp 384-well plates (Nunc) were coated with recombinant fusion protein comprising Histone H3 residues 1-15 fused to the Glutathione-S-transferase N-terminal. Plates were then blocked with a 1 mg / mL 1-block solution (Tropix cat # T2015 - highly purified form of casein) in phosphate buffered saline solution. Kinase reactions were performed in the wells of the ELISA plate by combining an appropriate amount of mutant Aurora A kinase with test compound and 30 μΜ ATP. The reaction buffer was 10X of Cell Signaling cat # 9802 supplemented with 1 μg / mL l-block. Reactions were stopped after 40 minutes by addition of 25 mM EDTA. After washing, substrate phosphorylation was detected by addition of sheep antiphosphohistone H3 (Ser 10) 6G3 mAb (Cell Signaling cat # 9706) and pAb-HRP (Amersham cat # NA931V), followed by colorimetric development. com TMB (3,3 ', 5,5'-tetramethylbenzidine from Kirkegaard & Perry Laboratories). After the adsorption reading, IC50 values were calculated using nonlinear curve fitting (XLfit software (ID Business Solution Ltd., Guilford, Surrey, UK)). Results are shown in Table 1.

Results: Table 1

<table> table see original document page 28 </column> </row> <table>

Antiproliferative activity

The activity of the compounds present as antiproliferative agents is demonstrated by the following biological assay:

CelITiter-GIo ™ Assay in HCT 116 cellsThe CelITiter-GIo ™ Luminescent Cell Viability Assay (Promega) is a homogeneous method of determining the number of viable cells in culture based on the quantification of ATP present, which signals the presence of metabolically active cells. active.

HCT 116 cells (human colon carcinoma, ATCC-No. CCI-247) were cultured in RPMI 1640 medium with GlutaMAX ™ I (Invitrogen, Cat-No. 61870-010), 2.5% Fetal Calf Serum (FCS) , Sigma Cat-No.F4135 (FBS)); 100Units / ml penicillian / 100Mg / ml streptomycin (= Invitrogen Pen / Strep Cat. No. 15140). For the assay, cells were seeded into 384-well plates, 1000 cells per well, same mean. The following day, test compounds were added at various concentrations ranging from 30 μΜ to 0.0015 μΜ (10 concentrations, diluted 1: 3). After 5 days, the CelITiter-GIo ™ assay was performed according to the manufacturer's instructions (Promega Luminescent CelITiter-GIo ™ Cell Viability Assay). In summary: the cell plate was equilibrated at room temperature for approximately 30 minutes and the CelITiter-GIo ™ reagent was added. The contents were carefully mixed for 15 minutes to induce cell lysis. After 45 minutes, the luminescent signal was measured on Victor 2, (Wallac multi-layer scanning spectrophotometer).

Details: 19. day:

Medium: RPMI 1640 with GlutaMAX ™ I (Invitrogen, Cat-No. 61870), 5% CFS (Sigma Cat. -Ng F4135), Pen / Estrep (Invitrogen, Cat No. 15140).

- HCT116 (ATCC-N9 CCI-247): 1000 cells at 60 μΙ per 384-well placard well (Greiner 781098, μΟΙβ3Γ white plate)

- After sowing, incubate the plates 24 h at 37 ° C, 5% CO 2,29. day: Induction (Treatment with compounds. 10 concentrations):

To achieve a final concentration of 30 μΜ as the highest concentration, 3.5 μΙ of 10 mM of compost raw material solution was added directly to 163 μΙ media. Then, step e) of the dilution procedure described below was followed. To reach the second highest concentration to the lowest concentration, a serial dilution with 1: 3 dilution steps was followed according to the procedure (a). -e) as described here below:

(a) For the second highest concentration, add 10 μΙ of 10 mM solution of compound feedstock to 20 μΙ dimethyl sulfoxide (DMSO)

b) dilute 8x 1: 3 (always 10 μΙ to 20 μΙ DMSO) in this DMSO dilution row (results in 9 wells with concentrations of 333.3 μΜ to 0.51 μΜ)

c) dilute each concentration 1: 47.6 (3.5 μΙ compound dilution in 163 μ meios media)

e) add 10 μΙ of each concentration in 60 μΙ media to the cell plate resulting in the final DMSO concentration: 0.3% in each well resulting in 10 final concentrations of compounds ranging from 30 μΜ to 0.0015 μΜ.

- Each compound is tested in triplicate.

- Incubate 120 h (5 days) at 37 ° C, 5% CO2

Analyze:

- Add 30 μΙ CelITiter-GIo ™ Reagent (prepared from ITiter-G Io ™ Ce Buffer and Promega-Acquired Celititer-GIo ™ Substrate) per well,

- stir 15 minutes at room temperature

- incubate another 45 minutes at room temperature without shaking

Measurement:

- Victor 2 Multi-Cavity Spectrophotometer (Wallac), Luminescence Mode (0.5 sec / reading, 477 nm)

- Determine IC50 using a nonlinear curve fitting (XLfit software (ID Business Solution Ltd., Guilford, Surrey, UK))

With all compounds, a significant inhibition of HCT 116 cell viability was detected, which is exemplified by the compounds shown in Table 2.

Results: Table 2 <table> table see original document page 31 </column> </row> <table>

The compounds according to this invention and their pharmaceutically acceptable salts may be used as medicaments, for example, in the form of pharmaceutical compositions. The pharmaceutical compositions may be administered orally, for example, as compressed tablets, coated tablets, dragees, hard gelatin capsules, solutions, emulsions or suspensions. However, administration may likewise be carried out rectally, for example, as suppositories, or parenterally, for example, as injection solutions.

The aforesaid pharmaceutical compositions may be obtained by processing the compounds of this invention with inert organic or pharmaceutically inert carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acids or their salts and the like may be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable vehicles for soft gelatin capsules are, for example, vegetable oils, waxes, fats, liquid and semi-solid polyols, and the like. Depending on the nature of the active substance, however, no carrier is normally required for soft gelatin capsules. Suitable vehicles for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable vehicles for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid liquid polyols, and the like.

The pharmaceutical compositions may furthermore contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, osmotic pressure varying salts, buffers, masking agents or antioxidants. They may likewise contain still other therapeutically valuable substances.

A pharmaceutical composition comprises, for example, the

following:

a) Tablet Formulation (Wet Granulation):

<table> table see original document page 32 </column> </row> <table>

Manufacturing Procedure:

1. Mix items 1, 2, 3 and 4 and granulate with purified water.

2. Dry the granules at 50 ° C.

3. Pass the granules through suitable grinding equipment.

4. Add item 5 and mix for three minutes; compress into a suitable machine.

<table> table see original document page 32 </column> </row> <table> Industrial procedure:

1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add items 4 and 5 and mix for 3 minutes.

3. Fill in a suitable capsule.c) Micro suspension

1. Weigh 4.0 g of glass beads into a custom GL 25.4 cm tube (the beads fill half of the tube).

2. Add 50 mg of compound, disperse with spatula and vortex.

3. Add 2 ml of gelatin solution (weight accounts: gelatin solution = 2: 1) and vortex.

4. Cap and wrap in aluminum plate for light protection.

5. Prepare a counterweight for the mill.

6. Grind for 4 hours, 20 / s in a Retsch mill (for some substances up to 24 hours at 30 / s).

7. Extract the bead suspension with two filter layers (100 μιη) into a filter holder coupled to a vial by centrifugation at 400g for 2 min.

8. Move the extract to the measuring cylinder.

9. Repeat the wash with small volumes (at this point, 1 ml steps) until the final volume is reached or the extract is clear.

10. Fill to final volume with gelatin and mix.

The following examples are provided to aid understanding of the present invention, the true scope of which is mentioned in the appended claims. It is understood that modifications may be made to the above-mentioned procedures without departing from the spirit of the invention.Experimental ProceduresA: Starting Materials

Preparation of 5,6-Diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one) 1-Ethyl-3,3-dimethyl-6-nitro-1,3-dihydro indol-2-one A solution of 3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (6g,

29.10 mmols) in anhydrous W / Î ± -dimethylformamide (DMF) (35 ml) was treated with sodium hydride. The resulting suspension was stirred for 1 hour at 60 ° C. A solution of bromoethane (2.17 mL, 3.17 g, 29.10 mmol) in DMF (10 mL) was added. The mixture was allowed to cool to room temperature and stirred for 1 hour. After removal of the solvent, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The extract was dried over Na 2 SO 4, evaporated and the crude product was purified by silica gel column chromatography. Elution with ethyl acetate / n-heptane (1: 3) yielded 5.94 g (87%) of a yellow solid.MS: M = 235.3 (ESI +)

1H-NMR (400 MHz. DMSO): δ (ppm) = 1.16 (t, 3H), 1.32 (s, 6H), 3.81 (q, 2H), 7.66 (d, 1H ), 7.86 (s, 1H), 7.97 (d, 1H)

ii) 6-Amino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one

In a solution of 1-ethyl-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (5.9 g, 25.19 mmols) in methanol / tetrahydrofuran (THF) (1: 1.80 ml), palladium on charcoal (10%, 1.2 g) was added and the hydrogenated mixture at room temperature for 4 hours. After filtration and evaporation of solvents 5.05 g (98%), 6-amino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one was isolated as a white solid.

MS: M = 205.0 (API +)

1H-NMR (400 MHz1 DMSO): δ (ppm) = 1.11 (t, 3H), 1.17 (s, 6H), 3.58 (q, 2H), 5.12 (br, 2H), 6.21 (d, 1H), 6.25 (s, 1H), 6.92 (d, 1H)

iii) N- (1-Ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -acetamide

A solution of 6-amino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one (5.05 g, 24.72 mmols) in acetic anhydride (80 ml) was stirred in room temperature for 4 hours. The mixture was poured into ice water (150 ml), allowed to warm to room temperature and stirred again for 2 hours. After extraction with ethyl acetate (3 x 100 ml), the combined organic layers were washed with sat. NaHCOs solution (3 x 100 ml), brine (100 ml) and dried over sodium sulfate. After removing the solvent, the crude product was purified by column chromatography over silica gel (1: 1 ethyl acetate / 1-heptane) yielding 5.6 g (91%) of N- (1-ethyl-3). 1,3-Dimethyl-2-oxo-2,3-dihydro-1 H -indol-6-yl) acetamide as light yellow solid.MS: M = 247.1 (API +)

1H-NMR (400 MHz, DMSO): δ (ppm) = 1.13 (t, 3H), 1.23 (s, 6H), 2.04 (s, 3H), 3.63 (q, 2H) , 7.12 (d, 1H), 7.23 (d, 1H), 7.37 (s, 1H), 9.97 (br, 1H)

iv) N- (1-ethyl-3,3-dimethyl-5-nitro-2-oxo-2,3-dihydro-1H-indol-6-yl) -acetamide

In a solution of N- (1-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-

indol-6-yl) acetamide (5.6 g, 22.73 mmol) in acetic anhydride (70 mL), nitric acid (100%, 1.96 g, 1.29 mL, 31.2 mmol) was added to 0 ° C. The mixture was stirred for 30 minutes, then poured into ice water (150ml). After stirring for 4 hours, the mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with solution of sodium hydroxide (1 M, 100 mL) and water (100 mL), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (1: 1 ethyl acetate / n-heptane) to yield 5.2 g (78%) of N- (1-ethyl-3,3-dimethyl). 5-nitro-2-oxo-2,3-dihydro-1H-indol-6-yl) acetamide as a yellow solid.MS: M = 292.0 (API +)

1H-NMR (400 MHz, DMSO): δ (ppm) = 1.16 (t, 3H), 1.31 (s, 6H), 2.13 (s, 3H), 3.71 (m, 2H) , 7.54 (s, 1H), 8.12 (s, 1H), 10.39 (br, 1H)

v) 6-Amino-1-ethyl-3,3-dimethyl-5-nitro-1,3-dihydro-indol-2-one

Λ / - (1-ethyl-3,3-dimethyl-5-nitro-2-oxo-2,3-dihydro-1 H -indol-6-yl) -

Acetamide (5.2 g, 17.85 mmol) was dissolved in ethanol (40 mL). After addition of hydrochloric acid (25%, 8 mL, 81.44 mmol), the mixture was stirred at reflux for 3 hours. The reaction mixture was allowed to cool to room temperature and then quenched with water (80 ml). The yellow precipitate was isolated by suction and washed with ethanol / water (1: 1). The solid was dissolved in ethyl acetate, dried over sodium sulfate and concentrated to yield 4.15 g (93%) 6-amino-1-ethyl-3,3-dimethyl-5-nitro-1,3-dihydro. indol-2-one as an orange solid. MS: M = 250.0 (API +) 1H-NMR (400 MHz. DMSO): δ (ppm) = 1.15 (t, 3H), 1.27 (s, 6H), 3.64 (m, 2H), 6.54 (s, 1H), 7.67 (br, 2H), 7.95 (s, 1H)

vi) 5,6-Diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one In a solution of 6-amino-1-ethyl-3,3-dimethyl-5-nitro 1,3-dihydro-indol-2-one (4.15 g, 16.65 mmol) in ethanol (80 mL), PtO 2 (0.4 g) was added and the mixture hydrogenated at room temperature for 3, After filtration and evaporation of solvents 3.25 g (89%), 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one was isolated as solid orange.MS: M = 220.0 (API +)

1H-NMR (400 MHz. DMSO): δ (ppm) = 1.10 (t, 3H), 1.13 (s, 6H), 3.53 (m, 2H), 4.08 (br, 2H) , 4.48 (br, 2H), 6.27 (s, 1H), 6.50 (s, 1H)

Preparation of 5,6-Diamino-1-isopropyl-3,3-dimethyl-1,3-dihydro-indol-2-one5,6-Diamino-1-isopropyl-3,3-dimethyl-1,3-dihydro indol-2-one was prepared in an analogous 6-step synthesis as described for 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one.MS: M = 234.1 (ESI +)

Preparation of 5,6-Diamino-3,3-diethyl-1-isopropyl-1,3-dihydro-indol-2-one) 3,3-Diethyl-5-nitro-1,3-dihydro-indol-2-one one

In a solution of 3,3-diethyl-1,3-dihydro-indol-2-one (10.0 g, 52.84 mmol, Mertens et al., J. Med. Chem. 30 (1987) 1279-1287) sulfuric acid conc. (50 ml), a mixture of slowly nitric acid (65%, 5.12 g, 3.63 ml, 52.84 mmol) and conc. (10 ml) at 0 ° C. After 2 hours at room temperature, the mixture was poured into ice water. The precipitate was filtered, washed with water and dried to yield 11.7 g of 3,3-diethyl-5-nitro-1,3-dihydro-indol-2-one (49.95 mmol, 94%).

MS: M = 235.1 (ESI +) ii) 3,3-Diethyl-1-isopropyl-5-nitro-1,3-dihydro-indol-2-one

A solution of 3,3-diethyl-5-nitro-1,3-dihydro-indol-2-one (11.7 g, 49.95 mmols) in anhydrous β / N-dimethylformamide (DMF) (60ml) was treated with sodium hydride (1.558 g, 64.93 mmol). The resulting suspension was stirred for 1 hour at 60 ° C. A solution of 2-iodopropane (4.99 ml, 8.49g, 49.95 mmol) was added. The mixture was kept at 60 ° C for a further 3 hours, allowed to cool to room temperature, poured into ice water. The precipitate was filtered, washed with water and dried to yield 12.6 g of 3,3-diethyl-1-isopropyl-5-nitro-1,3-dihydro-indol-2-one (45.60 mmols, 91%). MS: M = 277.1 (ESI +)

iii) 5-Amino-3,3-diethyl-1-isopropyl-1,3-dihydro-indol-2-one

In a solution of 3,3-diethyl-isopropyl-5-nitro-1,3-dihydro-indol-2-one (12.6 g, 45.60 mmol) in methanol / tetrahydrofuran (THF) (1: 1, 80 ml), palladium on charcoal (10%, 1.2 g) was added and the hydrogenated mixture at room temperature for 4 hours. After filtration of the catalyst, the solvent was evaporated and the residue triturated with isohexane to yield 9.7 g of 5-amino-3,3-diethyl-1-isopropyl-1,3-dihydro-indol-2-one (39 g). , 37 mmol, 86%).

MS: M = 247.1 (ESI +)

iv) N- (3,3-Diethyl-1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) acetamide

A solution of 5-amino-3,3-diethyl-1-isopropyl-1,3-dihydro-indol-2-one (9.7 g, 39.37 mmol) in acetic anhydride (57 mL) was stirred in room temperature for 4 hours. The mixture was poured into ice water, allowed to warm to room temperature and stirred again for 2 hours. After extraction with ethyl acetate, the combined organic layers were washed with aqueous 1 M NaOH solution and brine dried over sodium sulfate. After removal of the solvent, the crude product was triturated with isohexane to yield 10.4 g of N- (3,3-diethyl-1-isopropyl-2-oxo-2,3-dihydro-1H-indole -5-yl) acetamide (36.06 mmol, 91%) MS: M = 289.2 (ESI +)

v) N- (3,3-Diethyl-1-isopropyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl) -acetamide

In a solution of N- (3,3-diethyl-1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) acetamide (10.4 g, 36.06 mmols) in acid sulfuric conc. (50 ml) A mixture of nitric acid slowly (65%, 3.84 g, 2.72 ml, 39.67 mmols) and conc. Sulfuric acid was added. (10 ml) at 0 ° C. After 2 hours at room temperature, the mixture was poured into ice water. The precipitate was filtered off, washed with water and dried. The crude material was purified by silica gel chromatography (1: 1 isoexane / ethyl acetate) to yield 2.2 g of N- (3,3-diethyl-1-isopropyl-6-nitro-2-oxo-2,3). -dihydro-1H-indol-5-yl) acetamide (6.60 mmol, 18%) plus N- (3,3-diethyl-1-isopropyl-7-nitro-2-oxo-2,3-dihydro Unwanted -1H-indol-5-yl) acetamide (5.5 g).

MS: M = 332.2 (ESI-)

vi) 5-Amino-3,3-diethyl-1-isopropyl-6-nitro-1,3-dihydro-indol-2-one

N- (3,3-diethyl-1-isopropyl-6-nitro-2-oxo-2,3-dihydro-1 H -indol-5-yl) acetamide (2.2 g, 6.60 mmols) was dissolved in ethanol (50 ml). After addition of hydrochloric acid (25%, 3.2 mL, 33.0 mmol), the mixture was heated at reflux for 3 hours. Most of the solvent was evaporated and water was added. The mixture was weakly alkalized by addition of aqueous NaOH solution. The mixture was extracted with ethyl acetate, the combined organic phases were dried over magnesium sulfate and the solvent was evaporated to yield 1.9 g of 5-amino-3,3-diethyl-1-isopropyl-6. nitro-1,3-dihydro-indol-2-one (6.52 mmol, 99%).

MS: M = 290.1 (ESI-)

vii) 5,6-Diamino-3,3-diethyl-1-isopropyl-1,3-dihydro-indol-2-one

In a solution of 5-amino-3,3-diethyl-1-isopropyl-6-nitro-1,3-dihydro-indol-2-one (1.9 g, 6.52 mmol) in methanol / tetrahydrofuran (THF ) (1: 1.80 ml), palladium on charcoal (10%, 1.2 g) was added and the mixture hydrogenated at room temperature for 4 hours. After filtration, the solvent was evaporated and the residue triturated with isohexane to yield 1.7 g of 5,6-diamino-3,3-diethyl-1-isopropyl-1,3-dihydro-indol-2-one (6 , 50 mmol, 99%).

MS: M = 262.3 (ESI +)

1H-NMR (400 MHz, DMSO): δ (ppm) = 0.44 (t, 6H), 1.34 (d, 6H), 1.55 (q, 2H), 1.65 (q, 2H) , 4.40 (br, 4H), 4.45 (m, 1H), 6.42 (s, 1H), 6.46 (s, 1H)

Preparation of 5,6-Diamino-1,3,3-triethyl-1,3-dihydro-indol-2-one

5,6-Diamino-1,3,3-triethyl-1,3-dihydro-indol-2-one was prepared in an analogous 7-step synthesis as described for 5,6-diamino-3,3-diethyl-1-one. isopropyl-1,3-dihydro-indol-2-one.

MS: M = 248.1 (API +)

1H-NMR (400 MHz. DMSO): δ (ppm) = 0.43 (t, 6H), 1.08 (t, 3H), 1.55 (q, 2H), 1.63 (q, 2H) 3.54 (q, 2H), 4.10 (br, 2H), 4.48 (br, 2H), 6.27 (s, 1H), 6.43 (s, 1H) (5-Ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo [4,5-] indol-2-yl) -1H-indazol-5-carboxylic acid) 3-formyl-1 H-indazol-5-carboxylic

In a mixture of Indo-5-carboxylic acid (5.5 g, 0.0338 mol) in water (250 ml), NaNO2 (23.5 g, 0.338 mol) and hydrochloride solution (6N, 42 ml, 0.293) were added. mol). After 12 hours at room temperature, the precipitate was filtered off, washed with water (270 ml) and dried at 50 ° C to yield 5.36 g of 3-formyl-1H-indazol-5-carboxylic acid (0.028 mol , 83%), which was used without further purification.ii) 3- (5-Ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydroimidazo acid [4,5- /] indol-2-yl) -1 H-indazol-5-carboxylic

A mixture of 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one (1.1 g, 0.005 mol), 3-formyl-1H-indazole-5 acid Carboxylic acid (1.0 g, 0.005 mol) and sulfur (0.176 g, 0.005 mol) in DMF (25 ml) was heated under reflux for 4.5 hours. After cooling to room temperature, the reaction mixture was poured into water. After stirring for 15 minutes, the precipitate was filtered off, washed thoroughly with water and dried under vacuum in P 2 O 5 to yield 1.74 g of 3- (5-ethyl-7,7-dimethyl-6-oxo-3,5,6 acid). 7-tetrahydroimidazo [4,5- [] indol-2-yl) -1H-indazol-5-carboxylic acid (0.0044 mol, 89%) 20 MS: M = 390.4 (ESI +)

1H-NMR (400 MHz. DMSO): δ (ppm) = 1.21 (t, 3H), 1.34 (s, 6H), 3.79 (b, 2H), 7.04 and 7.46 ( s, 1H, two tautomeric forms), 7.51 and 7.84 (s, 1H, two tautomeric forms), 7.70 (d, 1H), 8.02 (d, 1H), 9.22 and 9.24 (s, 1H, two tautomeric forms), 12.87 (br, 1H), 13.05 and 13.11 (s, 1H, two tautomeric forms), 13.82 and 13.86 (s, 1H, two tautomeric forms).

In an analogous manner as described for 3- (5-ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo [4,5- / lindol-2-yl) -1H acid -indazol-5-carboxylic, the following starting materials were prepared from the appropriate indols: <table> table see original document page 40 </column> </row> <table>

Example 1

5-Ethyl-7,7-dimethyl-2- [5- (1H - [1,2,4] triazol-3-yl) -1H-indazol-3-yl] -5,7-dihydro-3H -imidazo [4,5-f] indol-6-one

i) 3- (5-Ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetraidiO-imidazo [4,5-f] indol-2-yl) -1 H- amide indazol-5-carboxylic

In a suspension of 3- (5-ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo [4,5-] indol-2-yl) -1 H- indazol-5-carboxylic acid (example 69, 500mg, 1.28 mmol) and DMF (1 drop) in THF (15 ml) at 0 ° C under a denitrogen atmosphere, oxalyl chloride (494 mg, 335 μΙ, 3) was added. , 89 mmol). The mixture was allowed to warm to room temperature and stirred for 5.5 hours. After 3 and 4 hours, 1 and 0.5 additional equivalents of oxalyl chloride were added. The reaction mixture was added to an aqueous ammonium solution (25%, 250 mL, 3339 mmol) stirred for 1 hour at room temperature. The aqueous phase was extracted three times with ethyl acetate and the solvent from the combined organic phases was evaporated. The residue was triturated with diisopropyl ether / n-heptane and water, and then dried in vacuo. 410 mg of 3- (5-ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo [4,5-] indol-2-yl) -1 H acid amide -indazol-5-carboxylic acid (1.056mmol, 82%) were obtained.

MS: M = 389.2 (ESI +)

1H-NMR (400 MHz. DMSO): δ (ppm) = 1.22 (t, 3H), 1.36 (s, 6H), 3.81 (q, 2H), 7.28 (br, 1H) 7.41 (br, 1H), 7.68 (br, 1H), 7.71 (m, 1H), 7.99 (m, 1H), 8.09 (br, 1H), 9.10 ( s, 1H), 14.04 (br, 1H)

ii) 3- (5-Ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo [4,5 - /] indol-2-yl) -1 H- acid dimethylaminomethylene amide indazol-5-carboxylic

A mixture of 3- (5-ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo [4,5-] indol-2-yl) -1 H acid amide -indazol-5-carboxylic acid (75 mg, 0.193 mmol) and dimethoxymethyl dimethylamine (336.4 mg, 2.653 mmols) were stirred at 20 ° C under a nitrogen atmosphere for 20 minutes. The reaction was quenched with water under ice cooling, and the resulting precipitate was filtered to yield 70 mg of 3- (5-ethyl-7,7-dimethyl-6-oxo-3,5,6,7) acid dimethylaminomethylene amide. crude -tetrahydroimidazo [4,5- [] indol-2-yl) -1H-indazol-5-carboxylic acid (70mg) which was used for the next step without further purification.

iii) 5-Ethyl-7,7-dimethyl-2- [5- (1H - [1,2,4] triazol-3-yl) -1 H-indazol-3-yl] -5,7-dihydro -3H-imidazo [4,5-f | indol-6-one

A mixture of 3- (5-ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo [4,5- / lindol-2-yl) -1H-indazole acid dimethylaminomethylene amide -5-carboxylic acid (70 mg, crude), hydrazone hydrate (41.3 mg, 0.825 mmol) and glacial acetic acid (350 μΙ) was heated at 75 ° C for one hour and then cooled to room temperature. environment. Water was added and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvent was evaporated. The residue was triturated with diethyl ether and purified by silica gel chromatography (9: 1 dichloromethane / methanol) to yield 41 mg of 5-ethyl-7,7-dimethyl-2- [5- (1H- [1 triazole-S-10-1H-indazol-S-yl-γ-dihydro-SH-imidazole-Î ± -flindol-e-one (0.0994 mmol, 63%) MS: M = 413.18 (ESI +)

1H-NMR (400 MHz. DMSO): δ (ppm) = 14.58 - 13.51 (bm, 2H), 13.01 (m, 1H), 9.22 (s, 1H), 8.49 ( s, 1H), 8.14 (d, 1H), 7.84 and 7.51 (s, 1H), 7.73 (d, 1H), 7.46 and 7.04 (s, 1H), 3 , 79 (m, 2H), 1.34 (s, 6H), 1.23 (m, 3H) Example 2

5-Ethyl-7,7-dimethyl-2- [6- (1H - [1,2,4] triazol-3-yl) -1H-indazol-3-yl] -5,7-dihydro-3H -imidazo [4,5-f] indol-6-one

In an analogous manner as described for example 1,5-ethyl-7,7-dimethyl-2- [6- (1H - [1,2,4] triazol-3-yl) -1H-indazol-3 -yl] -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one was prepared from 3- (5-ethyl-7,7-dimethyl-6-oxo-3 acid, 5,6,7-tetrahydroimidazo [4,5-f] indol-2-yl) -1H-indazol-6-carboxylic.MS: M = 413.3 (ESI +)

1H-NMR (400 MHz, DMSO): δ (ppm) = 13.71 (m, 2H); 13.01 (m, 1H); 8.58-8.52 (bm, 2H); 8.27 (s, 1H); 8.02 (d, 1H); 7.75 and 7.46 (s, 1H); 7.40 and 7.04 (s, 1H); 1.35 (s, 6H); 1.22 (t, 3H) Example 3

5-Ethyl-7,7-dimethyl-2- [5- (1H-tetrazol-5-yl) -1H-indazol-3-yl] -5,7-dihydro-3H-imidazo [4,5-f ] indol-6-one

A mixture of 3- (5-ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydroimidazo [4,5-f] indol-2-yl) -1H-indazol-5 -carbonitrile (55 mg, 0.15 mmol), trimethyl tin azity (123 mg, 0.6 mmol) and DMF (4 mL) is heated to 150 ° C for 3 days. The reaction mixture was cooled to room temperature, treated with water and evaporated to dryness. The residue was treated three times with ethanol, followed by evaporation of the solvent. The residue was triturated ethyl comacetate to yield 5-ethyl-7,7-dimethyl-2- [5- (1H-tetrazol-5-yl) -1H-indazol-3-yl] -5,7-dihydro-3H -imidazo [4,5-f] indol-6-one (58 mg, 0.14 mmol, 93%) MS: M = 414.15 (ESI +) 1H NMR (400 MHz. PMSO): δ (ppm) = 13.97 (m, 1H), 9.28 (s, 1H), 8.12 (d, 1H), 7.88 (d, 1H), 7.67 (m, 1H), 7.25 ( m, 1H), 3.80 (q, 2H), 1.35 (s, 6H), 1.22 (t, 3H)

Example 4

5-Ethyl-7,7-dimethyl-2- (6-thiophen-3-yl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6 -ona

i) 2- [6-Bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -5-ethyl-7,7-dimethyl-3- (2-trimethylsilanyl-ethoxymethyl) -5J -dihydro-3H-imidazo [4,5-f] in-one

A solution of 2- (6-bromo-1H-indazol-3-yl) -5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indol-6-one (860 mg, 2.027 mmol) in THF (15 mL) at 0 ° C under an argon atmosphere, was treated with tert-butoxide sodium (430 mg, 4.444 mmol). After one hour at 0 ° C (2-chloromethoxyethyl) trimethyl silane (1017.4 mg, 6.102 mmol) was added. After 2 hours, two additional equivalents (2-chloromethoxyethyl) trimethyl silane were added, and the reaction mixture was allowed to warm to room temperature.

After 1.5 hours, the reaction mixture was treated with water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was evaporated. The residue was purified by silica gel chromatography (ethyl acetate) to afford 2- [6-bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -5-ethyl-7,7- crude dimethyl-3- (2-trimethylsilanyl-ethoxymethyl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one (1798 mg) which was used for the next step.

ii) 5-Ethyl-7,7-dimethyl-2- [6-thiophen-3-yl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -3- (2-trimethylsilanyl) ethoxymethyl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one

In a solution of 2- [6-bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -5-ethyl-7,7-dimethyl-3- (2-trimethylsilanyl-ethoxymethyl) - 5,7-Dihydro-3H-imidazo [4,5-f] indol-6-one (120 mg, 0.175 mmol) in toluene (2 mL) and methanol (0.3 mL) under an argon atmosphere were added tetrakis (triphenylphosphin) palladium (20.2 mg, 0.017 mmol), thiophene-3-boronic acid (33.6 mg, 0.263 mmol) and saturated aqueous sodium bicarbonate solution (480 μΙ). After heating at 90 ° C for 5.5 hours, the reaction mixture was allowed to cool to room temperature and treated with water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was evaporated. The residue was purified by HPL chromatography to yield 5-ethyl-7,7-dimethyl-2- [6-thiophen-3-yl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -3- (2-trimethylsilanyl-ethoxymethyl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one (61.3 mg, 0.089 mmol, 51%).

iii) 5-Ethyl-7,7-dimethyl-2- (6-thiophen-3-yl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indole -6-one

A mixture of 5-ethyl-7,7-dimethyl-2- [6-thiophen-3-yl-1- (2-trimethylsilyl-ethoxymethyl) -1H-indazol-3-yl] -3- (2- trimethylsilanyl-ethoxymethyl) -5,7-dihydro-3H-imidazo [4,5-flindol-6-one (61.3 mg, 0.089 mmol), tetra-n-butylammonium fluoride (1M THF solution, 1.834 mL) and ethylenediamine (54.4 mg, 0.905 mmol) was heated to 70 ° C for 48 hours. The reaction mixture was allowed to cool to room temperature and treated with water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was evaporated. The residue was purified by HPL chromatography to yield 5-ethyl-7,7-dimethyl-2- (6-thiophen-3-yl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one (27.8 mg, 0.065mmol, 73%) MS: M = 426.2 (ESI-)

1H-NMR (400 MHz, DMSO): δ (ppm) = 1.22 (t, 3H), 1.35 (s, 6H), 3.80 (m, 2H), 7.04 and 7.74 ( s, 1H, two tautomeric forms), 7.42 (d, 1H), 7.70 (m, 3H), 7.89 (s, 1H), 8.03 (m, 1H), 8.50 (m , 1H), 12.96 (m, 1H), 13.58 (s, 1H)

In an analogous manner as described for example 4, the following examples 5-23 were prepared from 2- (6-bromo-1H-indazol-3-yl) -5-ethyl-7,7-dimethyl-5,7 -dihydro-3H-imidazo [4,5-f] indol-6-one and appropriate boronic acids respectively boronic acid esters: <table> table see original document page 45 </column> </row> <table> <table > table see original document page 46 </column> </row> <table> <table> table see original document page 47 </column> </row> <table> table see original document page 48 </ column > </row> <table>

In an analogous manner as described for example 4, the following examples 24-30 were prepared from 2- (5-bromo-1H-indazol-3-yl) -5-ethyl-7,7-dimethyl-5,7 -dihydro-3H-imidazo [4,5-f] indol-6-one and appropriate boronic acids respectively boronic acid esters:

<table> table see original document page 48 </column> </row> <table> <table> table see original document page 49 </column> </row> <table> Example 31

5-Ethyl-7,7-dimethyl-2- (6-phenyl-1H-indazol-3-yl) -57-hydroxy-3H-imidazo [4,5-f] indol-6-one

i) 5-Ethyl-7,7-dimethyl-2- [6- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) - 1H-indazol-3-yl] -3- (2%)

5,7-dihydro-3H-imidazo [4,5-f] indol-6-one

In a solution of 2- [6-bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -5-ethyl-77-dimethyl-3- (2-trimethylsilanyl-ethoxymethyl) -5, 7-Dihydro-3H-imidazo [4,5-f] indol-6-one (see example 4i, 400 mg, 0.584 mmol) in DMF (2 mL) under an argon atmosphere, bis (pinacolato) di -boro (164.6 mg, 0.648 mmol), potassium acetate (172 mg, 1.752 mmol) 1,1'-bis (diphenylphosphino) ferrocenopalladium (II) chloride dichloromethane (23.8 mg, 0.029 mmol) . After heating at 75 ° C for 14 hours, the reaction mixture was allowed to cool to room temperature and purified by silica gel chromatography (ethyl acetate) to yield 5-ethyl-7,7-dimethyl-2- [6- (4). 4,5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -3- (2-trimethylsilanyl-ethoxymethyl) ) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one (413 mg, 0.564 mmol, 97%).

ii) 5-Ethyl-7,7-dimethyl-2- [6-phenyl 1-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -3- (2-trimethylsilanyl-ethoxymethyl) - 57-dihydro-3H-imidazo [4,5-f] indol-6-one

In a solution of 5-ethyl-7,7-dimethyl-2- [6- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1- (2-trimethylsilanyl -ethoxymethyl) -1H-indazol-3-yl] -3- (2-trimethylsilanyl-ethoxymethyl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one (106.9 mg 0.166 mmol) in toluene (2 mL) and methanol (0.3 mL) under an argon atmosphere, were added bromo-benzene (35.8 mg, 0.228 mmol), tetrakis (triphenylphosphin) palladium (17 mg, 0.015 mmol) and saturated aqueous sodium bicarbonate solution (400 μΙ). After heating at 90 ° C for 6.5 hours, the reaction mixture was allowed to cool to room temperature and treated with water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was evaporated. The residue was purified by HPL chromatography to afford 5-ethyl-7,7-dimethyl-2- [6-phenyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -3- (2 -trimethylsilanyl-ethoxymethyl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one (39.5 mg, 0.058 mmol, 40%).

iii) 5-Ethyl-7,7-dimethyl-2- (6-phenyl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one

A mixture of 5-ethyl-7,7-dimethyl-2- [6-phenyl-1- (2-trimethylsilanyl)

ethoxymethyl) -1H-indazol-3-yl] -3- (2-trimethylsilanyl-ethoxymethyl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one (39.5 mg, 0.058 mmol), tetra-n-butylammonium fluoride (1M THF solution, 1.15 mL) and ethylenediamine (35 mg, 0.582mmol) was heated at 70 ° C for 48 hours. The reaction mixture was allowed to cool to room temperature and treated with water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was evaporated. The residue was purified by HPL chromatography to afford 5-ethyl-7,7-dimethyl-2- (6-phenyl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5 -f] indol-6-one (27.8 mg, 0.065 mmol, 73%).

In an analogous manner as described for example 31, the following examples 32-34 were prepared from 2- [6-bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -5-ethyl -7,7-dimethyl-3- (2-trimethylsilanyl-ethoxymethyl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one and aryl bromides

<table> table see original document page 51 </column> </row> <table> <table> table see original document page 52 </column> </row> <table>

In an analogous manner as described for example 31, the following examples 32-34 were prepared from 2- [5-bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -5-ethyl -7,7-dimethyl-3- (2-trimethylsilanyl-ethoxymethyl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one and appropriate aryl bromides:

<table> table see original document page 52 </column> </row> <table>

Example 37

5-Ethyl-7,7-dimethyl-2- [6- (1H-pyrazol-4-yl) -1H-indazol-3-yl] -5,7-dihydro-3H-imidazo [4,5-f ] indol-6-one

i) 4-lodo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-pyrazole

A solution of 4-iodo-1H-pyrazole (1000 mg, 5.104 mmols) in THF (20 mL) at 0 ° C under a nitrogen atmosphere was treated with sodium tert-butoxide (1079 mg, 11.23 mmols). . After one hour at room temperature, (2-chloromethoxyethyl) trimethyl silane (2253 mg, 15.31 mmol) was added. After 48 hours at room temperature, the reaction mixture was treated with water and the aqueous phase was extracted with ethyl acetate.

The combined organic phases were dried over MgSO4, and the solvent was evaporated. The residue was purified by HPL chromatography to afford 4-iodo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-pyrazole (1050 mg, 3.24 mmol, 63%).

ii) 5-Ethyl-7,7-dimethyl-2- [6- (1H-pyrazol-4-yl) -1H-indazol-3-yl] -5,7-dihydro-3H-imidazo [4, 5-f) indol-6-one

In an analogous manner as described for examples 32 ii) and iii), 5-ethyl-7,7-dimethyl-2- [6- (1H-pyrazol-4-yl) -1H-indazol-3-yl] -benzamide 5,7-Dihydro-3H-imidazo [4,5-f] indol-6-one was prepared from 4-iodo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-pyrazole and 5-ethyl-7 , 7-dimethyl-2- [6- (4,4,5,5-tetramethyl- [1,3,2] dioxa-borolan-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole -3-yl] -3- (2-trimethylethylethoxymethyl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one.

MS: M = 412.3 (ESI +)

1H-NMR (400 MHz. DMSO): δ (ppm) = 1.21 (t, 3H), 1.34 (s, 6H), 3.79 (m, 2H), 7.03 and 7.73 ( s, 1H, two tautomeric forms), 7.1 (d, 1H), 7.59 (d, 1H), 7.77 (s, 1H), 8.20 (s, 2H), 8.43 (d , 1H), 12.93 (s, 1H), 13.48 (s, 1H)

Example 38

5-Ethyl-7,7-dimethyl-2- (6-phenylethynyl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one

i) 5-Ethyl-7,7-dimethyl-2- [6-phenylethynyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -3- (2-trimethylsilanyl-ethoxymethyl) -5 7-dihydro-3H-imidazo [4,5-f] indol-6-one

A mixture of 2- [6-bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -5-ethyl-7,7-dimethyl-3- (2-trimethylsilanyl-ethoxymethyl) -5 7-dihydro-3H-imidazo [4,5-f] indol-6-one (150 mg, 0.219 mmol), ethinyl benzene (33.5 mg, 0.328 mmol), dichlorobis (triphenylphosphine) palladium (II) ( 8 mg, 0.011 mmol), copper (I) iodide (5 mg, 0.026 mmol) and diethylamine (426 mg, 600 μΙ, 5.82 mmols) under an argon atmosphere were heated at 60 ° C for 6 hours. The reaction mixture was allowed to cool to room temperature and treated with water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was evaporated. The residue was purified by HPL chromatography to afford 5-ethyl-7,7-dimethyl-2- [6-phenylethynyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -3- (2 -trimethylsilanyl-ethoxymethyl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one (103.5 mg, 0.146 mmol, 67%).

ii) 5-Ethyl-7,7-dimethyl-2- (6-phenylethynyl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one

In an analogous manner as described for example 4 iii), 5-ethyl-7,7-dimethyl-2- (6-phenylethynyl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4] , 5-f] indol-6-one was prepared from 5-ethyl-7,7-dimethyl-2- [6-phenylethynyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -3- (2-trimethylsilanyl-ethoxymethyl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-oneMS: M = 446.14 (ESI +)

1H-NMR (400 MHz. DMSO): δ (ppm) = 13.74 (m, 1H), 13.04 (m, 1H), 8.53 (m, 1H), 7.85 (s, 1H) , 7.73 and 7.47 (s, 1H), 7.63 (m, 2H), 7.46 (m, 4H), 7.38 and 7.04 (s, 1H), 3.79 (m, 2H), 1.34 (s, 6H), 1.21 (t, 3H) Example 39

5-Ethyl-7,7-dimethyl-2- {6- [2- (3-nitro-phenyl) -vinyl] -1H-indazol-3-yl} -5,7-dihydro-3H-imidazo [4 , 5-f] indol-6-one

i) 5-Ethyl-7,7-dimethyl-2- [6- [2- (3-nitro-phenyl) -vinyl] -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -benzamide 3- (2-trimethylsilanyl-ethoxymethyl) -5,7-dihydro-3imidazo [4,5-f] indol-6-one

A mixture of 2- [6-bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -5-ethyl-7,7-dimethyl-3- (2-trimethylsilanyl-ethoxymethyl) -5 7-dihydro-3H-imidazo [4,5-f] indol-6-one (50 mg, 0.073 mmol), 1-nitro-3-vinylbenzene (16.6 mg, 0.111 mmol), palladium acetate ( II) (0.5 mg, 0.0022 mmol), tri-o-tolylphosphine (1.5 mg, 0.0049), triethylamine (14.9 mg, 20.5 μΙ, 0.147 mmol) eDMF (0.5 ml) under an argon atmosphere, was heated at 140 ° C for 14 hours. The reaction mixture was allowed to cool to room temperature and treated with water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was evaporated. The residue was purified by HPL chromatography to afford 5-ethyl-7,7-dimethyl-2- [6- [2- (3-nitro-phenyl) -vinyl] -1- (2-trimethylsilanyl-ethoxymethyl) - 1H-indazol-3-yl] -3- (2-trimethylsilanyl-ethoxymph] indol-6-one (21.5 mg, 0.0285 mmol, 39%).

ii) 5-Ethyl-7,7-dimethyl-2- {6- [2- (3-nitro-phenyl) -vinyl] -1H-indazol-3-yl} -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one

In an analogous manner as described for example 4 iii), 5-ethyl-7,7-dimethyl-2- {6- [2- (3-nitro-phenyl) -vinyl] -1H-indazol-3-yl} -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one was prepared from 5-ethyl-7,7-dimethyl-2- [6- [2- (3-nitro -phenyl) -vinyl] -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -3- (2-trimethylsilanyl-ethoxymethyl) -5,7-dihydro-3H-imidazo [4,5 -f] indol-6-one.

MS: M = 493.30 (ESI +)

1H-NMR (400 MHz, DMSO): δ (ppm) = 13.67 (m, 1H), 12.99 (m, 1H), 8.55 -8.45 (m, 2H), 8.14 ( m, 2H), 7.83 (s, 1H), 7.77 - 7.70 (m, 3H), 7.69 and 7.45 (s, 1H), 7.64 - 7.56 (d, 1H), 7.39 and 7.03 (s, 1H), 3.79 (m, 2H), 1.34 (m, 6H), 1.22 (m, 3H)

Claims (11)

1. A compound according to formula I, wherein R1 is alkyl, R2 and R3 are alkyl, one of R4 and R5 is a) -X-heteroaryl, wherein heteroaryl is optionally substituted one to three times by alkyl, C (O) alkyl, alkoxy, fluorinated alkyl, fluorinated alkoxy, cyano, nitro, amino, alkylamino, dialkylamino or halogen; is optionally substituted one to three times by alkyl, C (O) alkyl, carboxy, NHC (O) alkyl, alkoxy, fluorinated alkyl, fluorinated alkoxy, cyano, hydroxy, nitro, amino, alkylamino, dialkylamino, C (O) alkyl- NH-, alkyl-S (O) 2 NH-, halogen, 2,4-dioxa-pentan-1,5-diyl or 2,5-dioxahexan-1,6-diyl; whereas phenyl is substituted once for phenyl; orc) -Z-cycloalkyl, and the other of R4 and R5 is hydrogen, X is a single bond or -C4 -C-, Y is a single bond, -CH = CH- or -C4 C-; Z is - CH = CH- and all pharmaceutically acceptable salts thereof. Compounds according to claim 1, wherein one of R 4 and R 5 is a) -X-heteroaryl, wherein the heteroaryl is optionally substituted one to three times by alkyl or alkoxy; phenyl is optionally substituted one to three times by alkyl, C (O) alkyl, alkoxy, fluorinated alkyl, nitro, dialkylamino, halogen or 2,4-dioxa-pentan-1,5-diyl; or wherein phenyl is substituted once for phenyl; orc) -Z-cycloalkyl and R4 and R5 are hydrogen, X is a single bond, Y is a single bond, -CH = CH- or -C4 -C-; eZ is -CH = CH-. Compounds according to any one of claims 1 or 2, wherein one of R 4 and R 5 is -X-heteroaryl, wherein heteroaryl is optionally substituted one to three times by alkyl or alkoxy and the other of R 4 and R 5 is hydrogen. Compounds according to any one of claims 1 or 2, wherein one of R 4 and R 5 is -Y-phenyl, wherein phenyl is optionally substituted one to three times by alkyl, C (C) alkyl- alkoxy, alkyl fluorinated, nitro, dialkylamino, halogen or 2,4-dioxa-pentan-1,5-diyl; or wherein phenyl is substituted once by phenyl, and the other of R4 and R5 is hydrogen. Compounds according to any one of claims 1 or 2, wherein one of R 4 and R 5 is -Z-cycloalkyl and the other of R 4 and R 5 is hydrogen. Compounds according to claim 1, selected from the group consisting of: 5-Ethyl-7,7-dimethyl-2- [5- (1H - [1,2,4] triazol-3-yl ) -1H-indazol-3-yl] -5,7-dihydro-3H-imidazo [4,5- [] indol-6-one; 5-Ethyl-7,7-dimethyl-2- [6- ( 1 H- [1,2,4] triazol-3-yl) -1H-indazol-3-yl] -5,7-dihydro-3H-imidazo [4,5-flindol-6-one; 5-Ethyl -7,7-dimethyl-2- [5- (1H-tetrazol-5-yl) -1H-indazol-3-yl] -5,7-dihydro-3H-imidazo [4,5- indol-6 -one; 5-Ethyl-7,7-dimethyl-2- (6-thiophen-3-yl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-flindol-2-one] 6-one; 5-Ethyl-7,7-dimethyl-2- [6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-yl] -5,7-dihydro 3H-imidazo [4,5-flindol-6-one; -5-ethyl-7,7-dimethyl-2- (6-pyridin-3-yl-1H-indazol-3-yl) -5,7-one dihydro-3H-imidazo [4,5-f] indol-6-one; -5-ethyl-2- [6- (6-methoxy-pyridin-3-yl) -1 / - / - indazol-3-yl ] -7,7-dimethyl-5,7-dihydro-3 / - / - imidazo [4,5 -]] indol-6-one; -5-Ethyl-77-dimethyl-2- (6-pyridin-4 -yl-1H-indazol-3-yl) -57-dihydro-3H-imidazflindol-6-one; -5-Ethyl-77-dimethyl-2- (6-thiophen-2-yl-1H-indazol-3-one) yl) -5J-dihydro-3H-imidazo [4,5-f] indol-6-one -5-Ethyl-2- [5- (6-methoxy-pyridin-3-yl) -1H-indazol-3-yl] -7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indol-6-one; compound with acetic acid; -5-Ethyl-7,7-dimethyl-2- (5-thiophen-3-yl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5 -f] indol-6-one; compound with acetic acid; -5-Ethyl-7,7-dimethyl-2- [5- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-yl] -5,7- dihydro-3H-imidazo [4,5-f] indol-6-one; compound with acetic acid; -5-Ethyl-7,7-dimethyl-2- (5-pyridin-3-yl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5 -f] indol-6-one; -5-ethyl-7,7-dimethyl-2- (6-pyrimidin-5-yl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one; -5-ethyl-77-dimethyl-2- (6-pyridin-2-yl-1H-indazol-3-yl) -57-dihydro-3H-imidazo [ 4,5-f] indol-6-one; -5-ethyl-77-dimethyl-2- (5-pyrimidin-5-yl-1H-indazol-3-yl) -57-dihydro-3H-imidazo [ [f] indol-6-one; -5-ethyl-7,7-dimethyl-2- (5-pyridin-2-yl-1 H - indazol-3-yl) -5,7-dihydro-3 / - / - Imidazo [4,5-flindol-6-one; -5-Ethyl-7,7-dimethyl-2- [6- (1H-pyrazol-4-yl) -1H-indazol-3-one yl] -5,7-dihydro-3H-imidazo [4,5-flindol-6-one; -2- [6- (4-Dimethylamino-phenyl) -1H-indazol-3-yl] -5-ethyl 7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5- [] indol-6-one; -2- [6- (4-acetylphenyl) -1H-indazol-3-yl] -5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-] indol-6-one; 4- [3- (5-Ethyl-7,7-dimethyl] 6-oxo-3) 5) 6,7-tetrahydroimidazo [4,5- indol-2-yl) -1H-indazol-6-yl] benzoic acid 2- (6-Benzo [ 1,3] dioxol-5-yl-1H-indazol-3-yl) -5-ethyl-77-dimethyl-5,7-dihydro -3H-imidazo [4,5 - /] indol-6-one 2- [6- (3-Dimethylamino-phenyl) -1H-indazol-3-imidazo [4,5 - /] indol-6-one 5-Ethyl-7,7-dimethyl-2- [6- (3-nitro-phenyl) -1H-indazol-3-yl] -5,7-dihydro-3H-imidazo [4,5- [] indol-6-one 2- [5- (4-Dimethylamino-phenyl) -1H-indazol-3-yl] -5-ethyl-77-dimethyl-57-dihydro-imidazo [4,5-flindol -6-one 2- [5- (3-Dimethylamino-phenyl) -1H-indazol-3-yl] -5-ethyl-77-dimethyl-57-dihydro-3H-imidazo [4,5-flindol-6 -one; 2- (5-Benzo [1,3] dioxol-5-yl-1H-indazol-3-yl) -5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo [ 4,5-flindol-6-one; compound with acetic acid; 5-Ethyl-77-dimethyl-2- (6-phenyl-1H-indazol-3-yl) -5,7-dihydro-3H-imidazo [4,5 - /] indol-6-one 2- [6- (3,5-Dimethoxy-phenyl) -1H-indazol-3-yl] -5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5- [] indol-6-one; 5-ethyl-7,7-dimethyl-2- [6 - ((E) -styryl) -1H-indazol-3-yl] -5,7-dihydro-3H-imidazo [4,5-] indol-6-one; 5-Ethyl-2- {6 - [(E) -2- (4-fluoro-phenyl) -vinyl] -1 / - / - indazol-3-yl } -7,7-dimethyl-5,7-dihydro-3 H - imidazo [4,5- indol-6-one; 2- [6 - ((E) -2-biphenyl-4-yl] vinyl) -1 / - / - indazol-3-yl] -5-ethyl-7,7-dimethyl-5,7-dihydro-3 / - / - imidazo [4,5 - /] indol-6-one; 5-Ethyl-2- {6 - [(E) -2- (4-methoxy-phenyl) -vinyl] -1H-indazol-3-yl} -7,7-dimethyl-5,7-dihydro-3H- imidazo [4,5- [] indol-6-one; 5-ethyl-7,7-dimethyl-2- {6 - [(E) -2- (4-trifluoromethyl-phenyl) -vinyl] -1 / - t-indazol-3-yl} -5,7-dihydro-3H-imidazo [4,5-flindol-6-one; 2- {6 - [(E) -2- (4-Chloro-phenyl) -vinyl ] -1H-indazol-3-yl} -5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-flindol-6-one; 5-Ethyl-2- {6 - [( E) -2- (3-Fluoro-phenyl) -vinyl] -1H-indazol-3-yl} -7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5- /] indole 6th -one; e5-Ethyl-7,7-dimethyl-2- {6 - [(E) -2- (3-nitro-phenyl) -vinyl] -1H-indazol-3-yl} -5,7-dihydro-3H -imidazo [4,5-flindol-6-one; compound with acetic acid; -5-Ethyl-7,7-dimethyl-2- (6-phenylethynyl-1 H -indazol-3-yl) -5,7-dihydro-3 H -imidazo [4, 5-f] indol-6-one; e-2- [6 - ((E) -2-Cyclohexyl-vinyl) -1H-indazol-3-yl] -5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo [4, 5 - /] indol-6-one. A process for preparing the compounds of formula I by reacting a compound of formula V, wherein R1, R2 and R3 are as defined above. for the formula Ina claim 1, one of Fg4 and Fg5 represents a functional group selected from bromine, iodine, boronic acids or boronic acid esters and the other of Fg4 and Fg5 is hydrogen with a compound of the formula Vla or Vlb, R4-G or R5-G Formula Vlaf Formula Vlb, wherein R5 and R4 have the above meaning for formula I in claim 1, and G represents a functional group selected from the group consisting of: hydrogen, bromine, iodine, boronic acids and boronic acid esters, provided that if G is bromine or iodine, Fg4 or Fg5 is boronic acid or a boronic acid ester, and if G is hydrogen, boronic acid or a boronic acid ester, Fg4 or Fg5 is bromine or iodine to producing the compounds of formula I <formula> formula see original document page 60 </formula> formula I, wherein R1, R2, R3, R4 and R5 have the above meaning for formula I in claim 1, b) isolating the compounds of formula I; and c) if desired, converting the compounds of formula I into their pharmaceutically acceptable salts. A pharmaceutical composition containing one or more compounds as defined in claims 1 to 6 together with pharmaceutically acceptable excipients. A pharmaceutical composition containing one or more compounds according to claims 1 to 6 as active ingredients together with pharmaceutically acceptable adjuvants for inhibiting tumor growth. Use of a compound as defined in claims 1 to 6 for the manufacture of corresponding medicaments for inhibiting tumor growth. Use of a compound as defined in claims 1 to 6 for inhibiting tumor growth.